Abstract Alzheimer?s disease (AD) is the most common cause of dementia among elderly patients afflicted by neurodegenerative diseases, affecting about 25 million people worldwide and regarded as the fourth most common cause of death. Significant accumulation in the brain of Amyloid ? (A?) is consistently observed in AD. Due to its accumulation in AD, removal of the toxic A? from the system is expected to benefit AD patients. Extensive efforts were devoted to developing therapeutic interventions targeting A? and its clearance to treat AD but with limited success. Ongoing modified attempts to target A? using anti-A? antibodies or small molecule inhibitors of A? production are yielding somewhat favorable success. Although anti-A? antibodies meet the desired goal, unintended immunological side-effects in patients has been a concern. We have developed and characterized a non-immune based retro-inverso peptide, Amytrap-1 with significant A? binding properties. We have shown that Amytrap can bind both soluble and less soluble forms of A? (A?40 and A?42) in vitro and that it can reduce A? plaque size and A? protein levels in the brain of a clinically relevant mouse model of AD and restore memory functions. We have also shown that immobilized Amytrap-1 peptide can bind and trap spiked A? from sera samples in a concentration dependent manner. Amytrap-1 peptide is stable due to its D-amino acid configuration and it is safe as it did not show any immune side effects in the AD mice. In this phase 1, we propose to develop an ex-vivo system that could selectively remove A? from the circulation without being systemically introduced into the patients. We plan to generate and test a prototype extracorporeal column named ?Amytrapper? to bind and remove A? from plasma. Currently there are no extracorporeal systems to treat AD patients. Amytrapper is first of its kind to treat AD. Amytrapper will be in the form of a cartridge containing a solid support chemically linked to Amytrap-1 peptide. We envision Amytrapper to be a part of a standard apheresis system, wherein plasma from AD patients is passed through to selectively sequester A?, and A?-free plasma re-enters the body. Reducing the circulatory A? will shift the amyloid equilibrium towards the periphery and thus will deplete brain A? burden. In this proof-of-concept study, we will develop and characterize Amyrapper and test its performance with plasma spiked with A?42. We will, in Aim 1, synthesize and characterize Amytrapper for A? binding efficiency; in Aim 2, evaluate sensitivity and specificity of Amytrapper (suspension format) to bind A? in plasma and in Aim 3, prepare and test Amytrapper prototype (column format) for its sequestering ability of A? in plasma. We are confident to succeed in this effort as we have designed an appropriate target product plan with defined goals and deliverables. Besides, we have lined up the right industry leaders who are currently marketing FDA approved apheresis columns for other indications as CRO?s to collaborate with us. In subsequent phase of the study, the device will be tested in a clinically relevant mouse model of AD followed by a first in human study.